Torsion dystonia is a movement disorder of unknown etiology characterized by sustained muscle contractions, frequently causing twisted and repetitive movements, or abnormal postures (Fahn, S., In Movement Disorders 2, C. D. Marsden, and S. Fahn, eds. (Boston: Butterworths), pp. 332-358 (1987)). Other symptoms include spastic torticollis, blepharospasm, writer's cramp, dysphonia, tremor and stuttering. About 66% of cases presenting with predominantly dystonic symptoms appear to be primary (idiopathic), with the remainder resulting as secondary symptoms of other neurologic disorders, such as GM.sub.2 gangliosidosis, Hallervorden Spatz, Parkinson disease, Huntington disease (ibid.) and Leber disease (Novotny, E. J. et al., Neurol. 36:1053-1060 (1986)), or the result of drug treatment or brain lesions, especially in the region of the basal ganglia. The disease frequency of idiopathic torsion dystonia (ITD) is unknown and probably underestimated, because the; disease is variable in its expression and some affected individuals do not come to medical attention. There are about 100,000 cases of dystonia in the United States, about half of which are thought to be hereditary. Disease frequency has been roughly estimated at 1/160,000 in the general population (Zeman, W. et al., Psychiatric Neurologia Neurochirurgia 77-121 (1967)) with a much higher frequency of 1/15,000-1/23,000 in Ashkenazi Jews (Zilber, N. et al., J. Med. Genet. 21:13-20 (1984); Eldridge, R., Neurol. 20:1-78 (1970)).
Different clinical subtypes of hereditary dystonia have been described in the general population based on age-of-onset, type of dystonic symptoms, and responsiveness to drugs (Segawa, M. et al., Adv. Neurol. 14:215-233 (1976); Lance, J. W., Annal. Neurol. 2:285-293 (1977); Quinn, N. P. et al., Adv. Neurol. 50:391-401 (1988); Kurlan, R. et al., Adv. Neurol. 50:385-389 (1988); Nygaard, T. G. et al., Adv. Neurol. 50:377-384 (1988); Forsgren, L. et al., Adv. Neurol. 50:83-92 (1988)). Almost all familial forms appear to follow an autosomal dominant mode of inheritance with reduced penetrance, with the exception being an X-linked Filipino form (Lee, L. V. et al., Adv. Neurol. 14:137-151 (1976); Fahn, S. et al., Ann. Neurol. 24:179 (1988)). In the Jewish, as well as some non-Jewish, populations cases with early onset cluster at age: 9 years and tend to progress to more generalized involvement, while cases with later onset cluster around age 48 years and tend to manifest signs of more restricted regions (Fahn, S., Clinical Neuropharm. 9 (Suppl. 2):S37-S48 (1986)). However, age-of-onset and clinical expressivity can vary remarkably within a family where presumably all cases have the same defective gene. Recent studies support an autosomal dominant mode of inheritance in the Jewish population with a penetrance of 31% (Bressman, S. B. et al., Adv. Neurol. 50:45-56 (1988b); Zilber, N. et al., J. Med. Genet. 21:13-20 (1984)), although earlier studies suggested an autosomal recessive mode of inheritance in some families (Eldridge, R., Neurol. 20:1-78 (1970)).
Dystonia in the Jewish population is a particularly important medical problem because of the presumed high frequency (1/10,000) of this apparently dominant allele (Zilber, N. et al., J. Med. Genet. 21:13-20 (1984)); the low penetrance of the allele which masks carrier status; and the usually early age of onset, which is associated with a more severe course of the illness (Fahn, S., Clinical Neuropharm. 9(Suppl. 2):S37-S48 (1986)). The similarity in clinical features and age of onset between dystonia in the Jewish and non-Jewish populations (Burke, R. E. et al., Movement Disorders 1:163-178 (1986); Brin, M. F. et al., Neurol. 37:137 (1987); Burke, R. E. et al., Neurol., (1989)), including the non-Jewish family studied here, suggests the possibility that the same gene is involved.
The molecular etiology of hereditary dystonia has been difficult to understand as only a limited number of neurochemical and neuropathological studies have been carried out on brain samples of deceased patients, and these patients have fallen into both hereditary and non-hereditary types of dystonia. The fact that a number of different types of lesions in the basal ganglia can cause dystonia serves to implicate this area of the brain, which is known to control involuntary movements (Calne, D. B. et al., Adv. Neurol. 50:9-33 (1988); Marsden, C. D. et al., Brain 108:461-483 (1985)). In addition, over 24 different hereditary conditions can manifest secondary dystonic symptoms (Fahn, S., In Movement Disorders 2, C. D. Marsden, and S. Fahn, eds. (Boston: Butterworths), pp. 332-358 (1987)). Together these findings suggest that dystonic symptoms can be elicited fairly specifically in rats by stereotactic injection of the N-terminal end of pro-opiomelanocortin into the locus coeruleus (Jacquet, Y. F. et al., Science 218:175-177 (1982)) or norepinephrine into the striatum, red nucleus, accumbens or thalamus (de Yebenes, J. G. et al., Neurol. 38(Suppl 1):207 (1988)). Recently, discrete neuropathologic changes, including neurofibrillary tangles, have been observed in the brain of a 29-year-old Jewish male (Hedreen, J. C. et al., Adv. Neurol. 50:123-130 (1988)); previous studies found no abnormalities in two cases of hereditary dystonia (Zeman, W., Neurol. 20(Part II):79-88 (1970)). Drug treatments that can induce dystonia symptoms in humans include L-DOPA, D-2 receptor antagonists and anticonvulsants (Fahn, S., In Movement Disorders 2, C. D. Marsden, and S. Fahn, eds. (Boston: Butterworths), pp. 332-358 (1987)). In some patients, drug treatment can alleviate symptoms, but in most forms of dystonia there is no consistent "best" treatment. Drugs which have proven useful in some patients include the anticholinergics, benzodiazepines and carbamazepine. Two potentially etiologically and genetically distinct forms of hereditary dystonia that do respond to specific pharmacotherapy are the dystonia-Parkinsonism complex which can be treated with levodopa (Nygaard, T. G. et al., Adv. Neurol. 50:377-384 (1988)), and myoclonic-dystonia which can be relieved by alcohol (Quinn, N. P. et aL, Adv. Neurol. 50:391-401 (1988)).
Linkage analysis using DNA polymorphisms provides a powerful means to find the chromosomal location of genes causing hereditary diseases in the human population when appropriate family material is available. Recent advances in this analysis include highly polymorphic markers conferred by variable number tandem repeat (VNTR) sequences scattered throughout the genome (Nakamura, Y. et al., Science 235:1616-1622 (1987); Jeffreys, A. J. et al., Nature 314:67-73 (1985)), and a large number of marker sequences spaced at known recombination intervals spanning essentially the entire human genome at .ltoreq.5 centiMorgan (cM) intervals (Donis-Keller, H. et aL, Cell 51:319-337 (1987); White, R. et al., Nature 313:101-105 (1985)). Using this approach the chromosomal locations of over 20 genes causing hereditary neurologic diseases have been established (see HHMI, Human Gene Mapping Library). For two of these diseases for which deletional mutations exist, retinoblastoma and Duchenne muscular dystrophy, this tocational information led to the discovery of the responsible gene, which in both cases encoded a previously undescribed protein (Lee, W. H. et al., Nature 329:642-645 (1987); Hoffman, E. P. et al., Cell 51:919-928 (1987)).
Until the present invention, the chromosomal location of the gene(s) causing torsion dystonia has not yet been identified. Using protein and restriction fragment length polymorphic (RFLP) markers, studies in a large non-Jewish family of French, English and American Indian descent, originally described by Johnson et al. (Arch. Neurol. 7:301-313 (1962)), excluded about 20% of the autosomal complement of the genome (Kramer, P. L. et al., Adv. Neurol. 50:57-66 (1988); Falk, C. T. et al., Adv. Neurol. 50:67-72 (1988)), including large regions of chromosomes 11p, 13q and 21q (Kramer, P. L. et al., Genet. Epidemiol. 4:377-386 (1987)), and the candidate genes pro-opimelanocortin and glutamic acid decarboxylase (Breakefield, X. O. et al., J. Neurogenet. 3:159.-175 (1986)). This family exhibits a form of dystonia which is consistent with an autosomal dominant mode of inheritance with reduced penetrance. The clinical syndrome and age-of-onset of dystonia in this family resemble that described for Jewish and non-Jewish families with pedigrees consistent with dominant inheritance (Burke, R. E. et al., Movement Disorders 1:163-178 (1986); Brin, M. F. et al., Neurol. 37:137 (1987); Burke, R. E. et al., Neurol., (1989)).
Research on the molecular etiology of dystonia has been confounded by the large number of hereditary and environmental factors that can produce dystonic symptoms and by the paucity of neuropathological and neurochemical studies on brains from affected individuals. The finding of a linked marker for one hereditary form of dystonia will help to resolve the number of different genes underlying hereditary dystonias. These markers can be used eventually to provide genetic counseling in some affected families. Most importantly, the delineation of the genomic region containing the dystonia gene will provide a means to eventually discover and characterize this gene and its encoded protein. The finding of linked markers will also make it possible to evaluate the role of gene(s) in this chromosomal region in other forms of hereditary dystonia, (Eldridge, R., Neurol. 20:1-78 (1970)), Swedish with late onset (Forsgren, L. et al., Adv. Neurol. 50:83-92 (1988)), dopa-responsive with features of Parkinsonism (Nygaard, T. G. et al., Adv. Neurol. 50:377-384 (1988)), paroxysmal (Bressman, S. B. et al., Adv. Neurol. 50:403-413 (1988a)), myoclonic-dystonia (Quinn, N. P. et al., Adv. Neurol. 50:391-401 (1988); Kurlan, R. et al., Adv. Neurol. 50:385-389 (1988)) and dystonia with diurnal fluctuations (Segawa, M. et al., Adv. Neurol. 14:215-233 (1976)).